P318: A DUAL ROLE FOR PSIP1 IN T-ALL
Authors: L. Demoen, F. Matthijssens, Z. Debyser, S. Goossens, P. Van Vlierberghe
Journal: HemaSphere (2022)

Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer characterized by the diffuse infiltration of malignant T-cell progenitors in the bone marrow. Currently, the cure rates have augmented to 80% for pediatric and 60% for adult T-ALL cases due to modern intensified chemotherapy treatments. These cure rates sadly come at the cost of severe side effects and current therapy still provides a poor outcome for primary therapy-resistant or relapse cases. Therefore, there is an urgent need for the identification of key drivers and pathways in T-ALL to develop targeted and less toxic therapies. PSIP1, a histone mark reader, was primarily found as a dependency factor in MLL-rearranged AML, which was dispensable for normal hematopoietic development, making it an interesting therapeutic target. Nevertheless, the identification of inactivating mutations and deletions in T-ALL patients and lower expression in all T-ALL subtypes, with exception of the TLX1-subtype, compared to normal T-cell subsets, is rather an indication that PSIP1 can also serve as a tumor suppressor in certain contexts. Aims: In pursuance of determining the role of PSIP1 in tumor initiation and maintenance in T-ALL, we studied the effect of loss of PSIP1 by utilizing several different T-ALL mice models and human cell lines. Methods: To identify the role of PSIP1 during tumor initiation, we crossed a conditional Psipfl/fl knock-out mouse model with two different spontaneous T-ALL mouse models. On the other hand, to unravel the consequences of losing PSIP1 expression during tumor maintenance a proliferation competition assay was performed and RNA-seq profiling was used to identify downstream targets of PSIP1. Furthermore, tamoxifen-inducible Psipfl/fl mouse cell lines were created from Lmo2-driven T-ALL mouse tumors to test the loss Psip1 during tumor maintenance both in vitro and in vivo. Results: A conditional Psipfl/fl knock-out mouse model was crossed with two different spontaneous T-ALL mouse models, namely the Notch1 independent Lck-Cretg/+ Ptenfl/fl model and the Notch1 dependent CD2-Lmo2tg/+ transgenic, which can also give rise to ETP-like murine T-ALL tumors. The loss of Psip1 was shown to significantly accelerate T-ALL development in both models, with a p-value of 0.0156 and 0.0002 (see figure) respectively. Interestingly, in contrast with the role of PSIP1 loss in tumor initiation, the loss of PSIP1 expression impaired cell proliferation in five different human T-ALL cell lines. Further, tamoxifen-inducible Psip1 knock-out mouse cell lines were established and are being used to further confirm the dependency role of Psip1 during tumor maintenance. Lastly, COX20, an assembly factor of the cytochrome c oxidase in the mitochondria, was found to be a downstream target of PSIP1 upon knock-down and could explain the impairment of proliferation upon the loss of PSIP1 in these cell lines. Image:Summary/Conclusion: Altogether, these data indicate that PSIP1 can exert a dual role in the context of T-ALL, either as a tumor suppressor gene during tumor initiation or as a dependency factor in tumor maintenance. Its dispensability for normal hematopoiesis and its dependency role during tumor maintenance, illustrate the potential of PSIP1 as a therapeutic target in T-ALL.